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Current Research and Scholarly Interests

Autism is characterized by core social deficits but the underlying pathophysiology of these impairments are poorly understood. My research involves: 1) identifying novel biomarkers of social impairments in preclinical models and autism patients, 2) testing how epigenetic control of these biomarkers contributes to autism risk and symptom severity, and 3) investigating how these biological measures predict treatment outcomes in individuals with autism.

Abstract

Experimentally naïve outbred rats display varying rates of locomotor reactivity in response to the mild stress of a novel environment. Namely, some display high rates (HR) whereas some display low rates (LR) of locomotor reactivity. Previous reports from our laboratory show that HRs, but not LRs, develop locomotor sensitization to a low dose nicotine challenge and exhibit increased social anxiety-like behavior following chronic intermittent nicotine training. Moreover, the hippocampus, specifically hippocampal Y2 receptor (Y2R)-mediated neuropeptide Y signaling is implicated in these nicotine-induced behavioral effects observed in HRs. The present study examines the structural substrates of the expression of locomotor sensitization to a low dose nicotine challenge and associated social anxiety-like behavior following chronic intermittent nicotine exposure during adolescence in the LRHR hippocampi. Our data showed that the expression of locomotor sensitization to the low dose nicotine challenge and the increase in social anxiety-like behavior were accompanied by an increase in mossy fiber terminal field size, as well as an increase in spinophilin mRNA levels in the hippocampus in nicotine pre-trained HRs compared to saline pre-trained controls. Furthermore, a novel, selective Y2R antagonist administered systemically during 1wk of abstinence reversed the behavioral, molecular and neuromorphological effects observed in nicotine-exposed HRs. These results suggest that nicotine-induced neuroplasticity within the hippocampus may regulate abstinence-related negative affect in HRs, and implicate hippocampal Y2R in vulnerability to the behavioral and neuroplastic effects of nicotine in the novelty-seeking phenotype.

Abstract

A rat model of the novelty-seeking phenotype predicts vulnerability to the expression of behavioral sensitization to nicotine, where locomotor reactivity to novelty is used to screen experimentally-naïve rats for high (HR) versus low (LR) responders. The present study examines the long-term neuropeptidergic and neuroplastic adaptations associated with the expression of locomotor sensitization to a low dose nicotine challenge and social anxiety-like behavior following chronic intermittent nicotine exposure during adolescence in the LRHR phenotype. Our data show that the expression of behavioral sensitization to nicotine and abstinence-related anxiety are detected in nicotine pre-exposed HRs even across a long (3 wks) abstinence. Moreover, these behavioral effects of nicotine are accompanied by a persistent imbalance between neuropeptide Y and corticotrophin releasing factor systems, and a persistent increase in brain-derived neurotrophic factor (BDNF) and spinophilin mRNA levels in the amygdala. Furthermore, treatment with the cannabinoid receptor 1 antagonist, AM251 (5 mg/kg) during a short (1 wk) abstinence is ineffective in reversing nicotine-induced anxiety, fluctuations in BDNF and spinophilin mRNAs, and the neuropeptidergic dysregulations in the amygdala; although this treatment is effective in reversing the expression of locomotor sensitization to challenge nicotine even after a long abstinence. Interestingly, the identical AM251 treatment administered during the late phase of a long abstinence further augments anxiety and associated changes in BDNF and spinophilin mRNA in the basolateral nucleus of the amygdala in nicotine pre-exposed HRs. These findings implicate long-lasting neuropeptidergic and neuroplastic changes in the amygdala in vulnerability to the behavioral effects of nicotine in the novelty-seeking phenotype.

Abstract

A rat model of novelty-seeking phenotype predicts vulnerability to nicotine relapse where locomotor reactivity to novelty is used to rank high (HR) versus low (LR) responders. Present study investigates implication of cannabinoid receptor 1 (CB1R) in the basolateral (BLA) and the central (CeA) nuclei of amygdala in behaviorally sensitizing effects of nicotine and accompanying social anxiety following juvenile nicotine training and a 1- or 3-wk injection-free period in the novelty-seeking phenotype. Sprague-Dawley rats were phenotype screened, and received four, saline (1 ml/kg; s.c) or nicotine (0.35 mg/kg; s.c) injections, followed by a 1- or 3-wk injection-free period. Subsequently, animals were challenged with a low dose of nicotine (0.1 mg/kg; s.c.), subjected to the social interaction test and sacrificed. In situ hybridization histochemistry was used to assess CB1R messenger RNA (mRNA) levels in the amygdala. Nicotine pre-trained HRs displayed expression of locomotor sensitization to nicotine challenge along with enhanced social anxiety compared to saline pre-trained controls following a 1- or 3-wk injection-free period. HR-specific behavioral effects were accompanied by decreased CB1R mRNA levels in the CeA and the BLA following a 1-wk injection-free period. Decreased CB1R mRNA levels in both compartments of the amygdala were also observed following nicotine challenge in saline pre-trained HRs after a 3-wk injection-free period compared to HRs after a 1-wk injection-free period. These findings show robust, long-lasting expression of behavioral sensitization to nicotine in HRs associated with changes in amygdalar CB1R mRNA as a potential substrate for abstinence-related anxiety.

Abstract

Experimentally naive rats show variance in their locomotor reactivity to novelty, some displaying higher (HR) while others displaying lower (LR) reactivity, associated with vulnerability to stress. We employed a chronic variable physical stress regimen incorporating intermittent and random exposures of physical stressors or control handling during the peripubertal-juvenile period to assess interactions between stress and the LRHR phenotype in depressive- and anxiety-like behaviors on the forced swim and social interaction tests, respectively. A decrease in immobility in the forced swim test along with a decrease in social contact in the social interaction test were observed in the juvenile HRs, coupled with increases in brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus and in the basolateral amygdala with chronic variable physical stress. In contrast, an increase in immobility in the forced swim test and a decrease in social contact was observed in the LR counterparts coupled with an increase in the BDNF mRNA in the basolateral amygdala following chronic variable physical stress. Furthermore, chronic physical stress led to increased H3 and H4 acetylation at the P2 and P4 promoters of the hippocampal BDNF gene in the HR rats that is associated with increased suprapyramidal mossy fibre (SP-MF) terminal field volume. In contrast, chronic variable physical stress led to decreased H4 acetylation at the P4 promoter, associated with decreased SP-MF volume in the LR rats. These findings show dissociation in depressive- and anxiety-like behaviors following chronic variable physical stress in the juvenile HR animals that may be mediated by increased levels of BDNF in the hippocampus and in the amygdala, respectively. Moreover, chronic variable physical stress during the peripubertal-juvenile period results in opposite effects in depressive-like behavior in the LRHR rats by way of inducing differential epigenetic regulation of the hippocampal BDNF gene that, in turn, may mediate mossy fibre sprouting.

Abstract

An outbred rat model of novelty-seeking phenotype has predictive value for the expression of locomotor sensitization to nicotine. When experimentally naïve rats are exposed to a novel environment, some display high rates of locomotor reactivity (HRs, scores ranking at top 1/3rd of the population), whereas some display low rates (LRs, scores ranking at bottom 1/3rd of the population). Basally, HRs display lower anxiety-like behavior compared to LRs along with higher neuropeptide Y (NPY) mRNA in the amygdala and the hippocampus. Following an intermittent behavioral sensitization to nicotine regimen and 1 wk of abstinence, HRs show increased social anxiety-like behavior in the social interaction test and robust expression of locomotor sensitization to a low dose nicotine challenge. These effects are accompanied by a deficit in NPY mRNA levels in the medial nucleus of the amygdala and the CA3 field of the hippocampus, and increases in Y2R mRNA levels in the CA3 field and corticotropin releasing factor (CRF) mRNA levels in the central nucleus of the amygdala. Systemic and daily injections of a Y2R antagonist, JNJ-31020028, during abstinence fully reverse nicotine-induced social anxiety-like behavior, the expression of locomotor sensitization to nicotine challenge, the deficit in the NPY mRNA levels in the amygdala and the hippocampus, as well as result an increase in Y2R mRNA levels in the hippocampus and the CRF mRNA levels in the amygdala in HRs. These findings implicate central Y2R in neuropeptidergic regulation of social anxiety in a behavioral sensitization to nicotine regimen in the LRHR rats.

Abstract

An outbred rat model of novelty-seeking phenotype can differentiate between rats that show high rates (high responders; HRs) versus low rates (low responders; LRs) of locomotor reactivity to a novel environment. In the present study, LR and HR rats were exposed to a regimen of environmental and social stimuli (ESS) consisting of 14 random exposures of isolation, crowding or novel environment, once per day during the peripubertal-juvenile period (postnatal days 28-41) or handled as controls. Twenty-four hours after the last ESS exposure or control handling, all animals were tested on the forced swim and social interaction tests for depressive-like and social anxiety-like behaviors respectively. The ESS exposure during the peripubertal-juvenile period led to antidepressive-like effects on the forced swim test associated with increase in acetylation of histones 3 and 4 at the promoter regions P2 and P4 of the brain-derived neurotrophic factor (BDNF) gene in the dorsal hippocampus of HRs. Moreover, epigenetic activation of the hippocampal BDNF in the HRs following ESS exposure was accompanied by increase in the supra-pyramidal mossy fibre (SP-MF) and total mossy fibre terminal field volumes compared to handled controls. These findings suggest that the ESS exposure in the peripubertal-juvenile period may constitute an example of environmental induction of the hippocampal BDNF, and may mimic behavioral effects of exogenous antidepressants in the HR phenotype.

Abstract

An outbred rat model of the novelty-seeking phenotype is used to study nicotine vulnerability, where experimentally naïve rats were phenotype screened as high or low responders (HRs or LRs, ranking in the upper or lower one-third of the population respectively) based on locomotor activity displayed in a novel environment. Following nicotine training and abstinence, HR animals pre-trained with nicotine showed expression of locomotor sensitization to nicotine challenge along with enhanced social anxiety-like behavior in the social interaction test compared to saline pre-trained controls. HR rats also showed a downregulation in neuropeptide Y (NPY) mRNA levels in the medial nucleus of amygdala and the CA1 field of the hippocampus, an upregulation in Y2 mRNA levels in the CA3 field of the hippocampus, and an upregulation in the corticotropin releasing factor (CRF) mRNA levels in the central nucleus of the amygdala. These findings implicate dysregulations in the NPY-CRF systems in the HR hippocampus and amygdala associated with the emergence of social anxiety-like behavior, and a novel Y2R-mediated pathway in nicotine relapse.

Abstract

There are marked individual differences in the efficacy of mainstream nicotine cessation agents in preventing relapse. A rat model of novelty-seeking phenotype was reported to have predictive value for psychostimulant taking behavior where locomotor reactivity to novelty is used to rank high (HR, highest 1/3) versus low (LR, lowest 1/3) responsiveness to novelty in outbred rats. We tested the hypothesis that a cannabinoid receptor (CB) 1 antagonist that is in clinical trials for smoking cessation may reverse behaviorally sensitizing effects of nicotine in HRs and repeated nicotine-induced elevations in hippocampal 5HT.Adolescent LRHR rats underwent intermittent behavioral sensitization to nicotine regimen with or without a CB1 receptor antagonist AM251 or bupropion treatment following nicotine training during 1 week of nicotine-free period. Expression of behavioral sensitization to nicotine was assessed in response to a low-dose nicotine challenge. Using the same sensitization regimen and therapeutic treatments, hippocampal 5HT levels were measured via in vivo microdialysis in response to the nicotine challenge.HR but not LR animals showed behavioral sensitization to a low-dose nicotine challenge following intermittent nicotine training and 1 week of injection-free period. AM251 (5 mg/kg, i.p.) but not bupropion administration during injection-free period successfully reversed locomotor sensitization to nicotine challenge in HRs. AM251 treatment also reversed nicotine-induced elevations in extracellular 5HT in the HR hippocampal hilus.These data suggest that CB1 antagonists may prevent locomotor sensitization to nicotine and reverse nicotine-induced elevations in hippocampal 5HT in high novelty seekers.